The serotonin neurotransmitter system is known to regulate emotion, anxiety states and cognition. Moreover, altered serotonin transmission is hypothesized to be involved in the etiology and treatment of mood and anxiety disorders, and neurodegenerative diseases including Alzheimer's disease. This project is designed to take advantage of the high temporal and spatial resolution afforded by carbon fiber microelectrode voltammetry analytical methods to characterize changes in serotonin neurotransmission in three important human and mouse models with direct relevance to psychiatric and degenerative disorders. The proposed research will: (1) Use high-speed chronoamperometry to evaluate differences in the kinetics of serotonin reuptake in human lymphoblast cell cultures derived from individuals with variable serotonin transporter expression driven by two common promoter polymorphisms (5-HTTLPR and rs25531) in combination with an lle425Val coding region substitution mutation found in rare familiar forms of obsessive compulsive disorder;and (2) Employ fast cyclic voltammetry to characterize alterations in the dynamics of serotonin release and reuptake in vivo in serotonin transporter knockout mice and brain-derived neurotrophic factor (BDNF) knockout mice. Our overarching hypothesis states that potentially subtle but biologically important changes in serotonergic neurotransmission occur in mice and humans with altered serotonin transporter expression. Further, we theorize that changes in serotonin transmission underlie age-related degenerative loss of serotonergic innervation in mice with reduced BDNF. We postulate that application of fast electrochemical methods is necessary to detect these changes in brain neurotransmission, which are fundamental to the investigation of basic and disease-related processes. This outcome of these studies will reveal the extent to which voltammetric techniques are able to differentiate altered serotonin neurotransmission in genetically engineered mice and human cells with genetic alterations important for advancing our knowledge of the pathogenesis and treatment of psychiatric and neurodegenerative diseases.